IL6 mediated cFLIP downregulation increases the migratory and invasive potential of triple negative breast cancer cells

Abstract

c-FLIP (cellular FLICE-Like Inhibitor of Apoptotic protein) which belongs to the negative regulators of the death receptor pathway, control apoptosis in a number of cancers. literatures suggest that its overexpression facilitate cancer progression and also helps in the drug resistance. However, there is a very few data available to show how it control metastasis. Moreover, how cFLIP is regulated during the progression of cancer into advanced stage and its mechanism of action on tumor cell migration and invasion is yet to be known. Our TCGA data analysis has shown that cFLIP is downregulated in many cancers, including breast cancer, especially at the later stages. when, we analysed and compared early-stage breast carcinoma cell line MCF7 (luminal) and advanced stage triple negative cell line MDAMB-231, which is highly metastatic, we found a negative correlation between cFLIP expression and metastasis. Our results indicated that Il6, one of the most prominent cytokines inside tumor microenvironment, activated p38 and the later helped in cFLIP downregulation in MDA-MB-231 cell line. Moreover, we have found that cFLIP negatively regulated autophagy and this autophagy downregulation resulted in decrease in metastasis. Thus, we have shown, for the first time, a complete interconnecting pathway in which IL6 mediated p38 activation directly influences metastasis by regulating autophagy via cFLIP downregulation.